Tardive dyskinesia (TD) is a chronic disorder of the nervous system, characterized by involuntary jerky movements of the mouth, tongue, and facial muscles. In severe cases, TD may be characterized by wormlike (athetoid) movements of the extremities resulting in a drunken-appearing gait. The disorder is an extrapyramidal movement disorder associated with prolonged use of antipsychotic (neuroleptic) drugs. TD may manifest or worsen in severity even after a patient ceases use of neuroleptic agents. TD may become irreversible despite cessation of neuroleptic treatment.
The cumulative incidence of TD in patients exhibiting a first episode of schizophrenia who have undergone a four-year course of neuroleptic treatment is 16.5% (Chakos et al., Arch. Gen. Psychiatry 53:313,1996). The cumulative incidence is substantially higher in older people and in those being treated for conditions other than schizophrenia (see, e.g., Hayashi et al., Clin Neuropharmacol 19:390, 1996, Jeste et al., Arch. Gen. Psychiatry 52:756, 1995).
Other extrapyramidal syndromes associated with prolonged use of neuroleptics include dystonias, drug-induced parkinsonianism (as opposed to the idiopathic variety) and akathisia or akinesia. Cognitive disorders are also associated with tardive dyskinesia, and may include impairment in attention, concentration, or other cognitive functions (see, e.g., Sachdev et al., Acta Psychiatr Scand 93:451, 1996; Waddington & Youssef, Psychol Med. 26:681, 1996; Swartz, Neuropsychobiology 32:115, 1995).
While the pathophysiologic mechanism of tardive dyskinesia is unknown, there is speculation that chronic or prolonged administration of neuroleptics, which act by blocking dopamine receptors (e.g., amoxapine, chlorpromazine, fluphenazine, halopridol, one notable exception being clozapine), results in hypersensitivity or up-regulation of dopamine receptors in the basal ganglia of the brain (see e.g., Andrews, Can J Psych 39:576, 1994; Casey, D. E. in Psychopharmacology: The Fourth Generation of Progress, Raven Press, 1995). Drugs that increase or enhance dopamine response, especially indirect dopamine agonists, can aggravate the disorder. Many psychiatrists avoid using dopamine agonist anti-Parkinson drugs in neuroleptic therapy because of a concern that increased dopamine will aggravate tardive dyskinesia. (Bezchibnyk-Butler & Remington, Can J. Psych. 39:74, 1994).
Glutamate-related excitotoxic damage to the basal ganglia has also been suggested as a potential cause of irreversible tardive dyskinesia (Andreasen & Jorgensen 1994).
While recent research suggest that Vitamin E can reduce symptoms of the disorder modestly (Lohr & Caliguiri, J Clin Psychiatry 57;167, 1996; Dabiri et al. 1994), there is no generally accepted treatment for either the movement or cognitive disorders associated with TD.
Memantine is a drug approved in Europe for treatment of Parkinson's disease. Memantine, a congener of amantadine, is a N-methyl-D-aspartate type (NMDA) receptor antagonist as well as a dopamine agonist. Although memantine has been reported to alleviate some of the dyskinetic movements that can be seen in treated Parkinson's disease, there are no reports of its use in humans to treat tardive dyskinesia, and at least one notable expert in the field of TD has expressed surprise that any anti-Parkinson's drug would be an effective agent against TD (Jeste, pers. comm.).
In U.S. Pat. No. 4,122,193, it is reported that 1,3,5-trisubstituted adamantane, including 1-amino-3,5-dimethyl-adamantane is useful in the treatment of hyperkinesis in rats. The agent is also recommended as a treatment generally for hyperkinesis, albeit in the context of Parkinson's as well as head tremors, thalmic tension conditions and spastic conditions, and for the activation of akinetic cerebroorganic conditions. It is notable that, unlike TD, these conditions are not thought to be aggravated by dopamine agonists. Moreover, there is no recognition in the reference that 1-amino-3,5-dimethyl-adamantane acts as a NMDA-receptor antagonist. Instead, disclosure indicates that 1,3,5-trisubstituted adamantane compounds "influence catecholamine metabolism, for instance by freeing dopamine or stimulating the receptors". This latter aspect suggests that the authors did not recognize that memantine could be an effective treatment of TD, for which administration of a dopamine agonist goes against expert opinion.
An object of this invention is to develop methods for treating tardive dyskinesia using NMDA receptor antagonists. Another object of this invention to develop new methods to treat hyperkinesia associated with tardive dyskinesia. More particularly, it is an object of the invention to reduce the severity and duration of involuntary movements associated with tardive dyskinesia. More particularly, it is the object of this invention to develop methods of treating tardive dyskinesia which utilize NMDA-receptor antagonists as a therapeutic approach.
Another object of the invention is to develop new methods for improving cognitive function in patients exhibiting TD, specifically to increase the attention span, concentration span, memory and everyday functional performance as measured both subjectively and objectively. The latter may be demonstrated using standard neuropsychological tests such as those assessing reaction time and short-term memory.
Another object of the invention is to develop new methods of treating tardive dyskinesia that act in a neuroprotective manner to reduce or prevent glutamate-related excitotoxic damage to the basal ganglia.